Depletion of Cytochrome P-450 by Thyroid Hormone and Cobalt-Protoporphyrin IX in Rat Liver: Evidence that Susceptibility Varies among Forms of the Heme Protein

Rosenberg, Daniel W.; Drummond, George I.; Smith, Terry J.

doi:10.1159/000139367

Cited by 5 publications

(3 citation statements)

References 13 publications

(20 reference statements)

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“…Another possible explanation for the reduced effect of CoPP on immune cells compared with CO therapy could be the occurrence of secondary side effects due to chronic HO‐1 induction. The subsequent increase of haem degradation products after HO‐1 induction may be harmful to cells, limiting the beneficial immunosuppressive effect of CoPP‐induced CO release …”

Section: Discussionmentioning

confidence: 99%

Carbon monoxide exposure improves immune function in lupus‐prone mice

et al. 2013

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SummarySystemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple alterations affecting the normal function of immune cells, such as lymphocytes, dendritic cells (DCs) and monocytes. Although the understanding of autoimmunity has significantly increased, the breakthrough in effective therapies has been modest, making necessary the development of new therapeutic strategies. Here we propose that a new potential target for therapy is haem oxygenase-1 (HO-1), an enzyme that catalyses the degradation of the haem group into biliverdin, carbon monoxide (CO) and Fe 2+ . These products exhibit immunosuppressive and anti-inflammatory effects, which can contribute to improving tolerance during organ transplantation. Because HO-1 is highly expressed by immune cells involved in SLE pathogenesis, such as monocytes and DCs, we evaluated whether induction of HO-1 expression or the administration of CO could ameliorate disease in the FccRIIb knockout (KO) mouse model for SLE. We found that CO administration decreased the expansion of CD11b + cells, prevented the decline of regulatory T cells and reduced anti-histone antibodies observed in untreated FccRIIb KO mice. Furthermore, CO-treated animals and HO-1 induction showed less kidney damage compared with untreated mice. These data suggest that HO-1 modulation and CO administration can ameliorate autoimmunity and prevent the lupus symptoms shown by FccRIIb KO mice, highlighting HO-1 as a potential new target for autoimmune therapy.

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Section: Discussionmentioning

confidence: 99%

Carbon monoxide exposure improves immune function in lupus‐prone mice

et al. 2013

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“…Hypothyroidism, a condition of thyroid hormone deficiency is quite prevalent, affecting about 1~2% of the general population. Among a number effects of hypothyroidism, animal data have shown that thyroid dysfunction can alter the expression of various drug-metabolizing enzymes, such as cytochrome P450s (CYPs), sulfotransferases, and uridine 5'-diphosphate-glucuronosyltransferases (Rosenberg et al ., 1995; Webb et al ., 1996; Badger et al ., 1998; Liddle et al ., 1998). CYPs are rate-limiting for drug metabolism and their induction accelerates metabolic clearance of a drug or its metabolites, while decreased CYP activity can lead to elevated accumulation of the xenobiotics, with potentially harmful effects.…”

Section: Introductionmentioning

confidence: 99%

Opposing regulation of cytochrome P450 expression by CAR and PXR in hypothyroid mice

Park

Lee

et al. 2012

Toxicology and Applied Pharmacology

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Clinical hypothyroidism affects various metabolic processes including drug metabolism. CYP2B and CYP3A are important cytochrome P450 drug metabolizing enzymes that are regulated by the xenobiotic receptors constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2). We evaluated the regulation of the hepatic expression of CYPs by CAR and PXR in the hypothyroid state induced by a low-iodine diet containing 0.15% propylthiouracil. Expression of Cyp3a11 was suppressed in hypothyroid C57BL/6 wild type (WT) mice and a further decrement was observed in hypothyroid CAR-/- mice, but not in hypothyroid PXR-/- mice. In contrast, expression of Cyp2b10 was induced in both WT and PXR-/- hypothyroid mice, and this induction was abolished in CAR-/- mice and in and CAR-/- PXR-/- double knockouts. CAR mRNA expression was increased by hypothyroidism, while PXR expression remained unchanged. Carbamazepine (CBZ) is a commonly used antiepileptic that is metabolized by CYP3A isoforms. After CBZ treatment of normal chow fed mice, serum CBZ levels were highest in CAR-/- mice and lowest in WT and PXR-/- mice. Hypothyroid WT or PXR-/- mice survived chronic CBZ treatment, but all hypothyroid CAR-/- and CAR-/- PXR-/- mice died, with CAR-/-PXR-/- mice surviving longer than CAR-/- mice (12.3 ±3.3 days vs. 6.3 ±2.1 days, p=0.04). All these findings suggest that hypothyroid status affects xenobiotic metabolism, with opposing responses of CAR and PXR and their CYP targets that can cancel each other out, decreasing serious metabolic derangement in response to a xenobiotic challenge.

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“…Upon birth, there is a surge in blood levels of T4 and T3 which stimulate gluconeogenesis in the liver 111 . Thyroid dysfunction profoundly alters the expression of many key drug metabolizing enzymes and transporters in liver, kidney, and intestine 112 , 113 , 114 , 115 . Thyroid hormone (TH) is also important in regulation of hepatic lipid metabolism 116 .…”

Section: Factors Modulating Hnf4 α Activitymentioning

confidence: 99%

Crosstalk of HNF4 α with extracellular and intracellular signaling pathways in the regulation of hepatic metabolism of drugs and lipids

Lü

2016

Acta Pharmaceutica Sinica B

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The liver is essential for survival due to its critical role in the regulation of metabolic homeostasis. Metabolism of xenobiotics, such as environmental chemicals and drugs by the liver protects us from toxic effects of these xenobiotics, whereas metabolism of cholesterol, bile acids (BAs), lipids, and glucose provide key building blocks and nutrients to promote the growth or maintain the survival of the organism. As a well-established master regulator of liver development and function, hepatocyte nuclear factor 4 alpha (HNF4α) plays a critical role in regulating a large number of key genes essential for the metabolism of xenobiotics, metabolic wastes, and nutrients. The expression and activity of HNF4α is regulated by diverse hormonal and signaling pathways such as growth hormone, glucocorticoids, thyroid hormone, insulin, transforming growth factor-β, estrogen, and cytokines. HNF4α appears to play a central role in orchestrating the transduction of extracellular hormonal signaling and intracellular stress/nutritional signaling onto transcriptional changes in the liver. There have been a few reviews on the regulation of drug metabolism, lipid metabolism, cell proliferation, and inflammation by HNF4α. However, the knowledge on how the expression and transcriptional activity of HNF4α is modulated remains scattered. Herein I provide comprehensive review on the regulation of expression and transcriptional activity of HNF4α, and how HNF4α crosstalks with diverse extracellular and intracellular signaling pathways to regulate genes essential in liver pathophysiology.

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Depletion of Cytochrome P-450 by Thyroid Hormone and Cobalt-Protoporphyrin IX in Rat Liver: Evidence that Susceptibility Varies among Forms of the Heme Protein

Cited by 5 publications

References 13 publications

Carbon monoxide exposure improves immune function in lupus‐prone mice

Carbon monoxide exposure improves immune function in lupus‐prone mice

Opposing regulation of cytochrome P450 expression by CAR and PXR in hypothyroid mice

Crosstalk of HNF4 α with extracellular and intracellular signaling pathways in the regulation of hepatic metabolism of drugs and lipids

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